Note: Descriptions are shown in the official language in which they were submitted.
i
CA 02390132 2002-05-02
1
"Method for film-coating tablets"
The present invention relates, in general, to
a method for film-coating tablets.
In particular, the invention relates to a
method for film-coating tablets using a solvent brought
to supercritical pressure, that is to say a fluid in a
supercritical state, or using a subcritical liquid,
this being in order to obtain tablets which are easy to
preserve and to use, in particular for therapeutic
purposes.
For many years, the protection of tablets
intended for various uses and in particular for.
therapeutic uses in human or veterinary pharmacy has
been provided by means of a film-coating. This in fact
involves a coating capable of avoiding disintegration
of these tablets while limiting their absorption of
moisture from the air which would irreversibly impair
them and would prevent their good preservation under
the usual domestic conditions. Some of these coatings
also have an important role on the rate of assimilation
of the active ingredients) in the body. This film
coating involves mixtures of well known compounds, such
as cellulose derivatives, some acrylic or methacrylic
polymers or copolymers and polyethylene glycol, as well
as inorganic agents such as talc or titanium dioxide,
and colorings. These film-coating agents are suspended
in a liquid which is either water when there is no
CA 02390132 2002-05-02
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incompatibility with the components of the tablets, and
in particular with the active ingredients) which are
contained therein, or an organic solvent such as
dichloromethane. This film-coating operation is
generally carried out in rotating cylinders with a
horizontal axis in which the tablets are constantly
stirred and subjected to a very fine spray of the
suspension or of the solution of the mixture of the
film-coating agents in the chosen solvent.
However, the above methods for the film-
coating of tablets are not without disadvantages. They
indeed require the handling of organic solvents, in
particular of halogenated solvents and cause the
emission of fumes of potentially toxic organic solvents
the traces of which also remain in the film-coated
tablets.
Moreover, the film-coating methods using an
aqueous solution or suspension require a drying phase
which can last more than 10 hours in some cases.
The search for a method for the film-coating
of tablets, which is capable of avoiding the
disadvantages of the previous methods while allowing
its use in systems or plants which are generally used
in conventional film-coating methods, remains of utmost
interest.
It is known that a fluid in supercritical
state, that is to say in a state characterized either
CA 02390132 2002-05-02
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by a pressure and a temperature which are respectively
greater than the critical pressure and temperature in
the case of a pure substance, or by a representative
point (pressure, temperature) situated beyond the
envelope of the critical points represented on a
diagram (pressure, temperature) in the case of a
mixture, exhibits, for very many substances, a high
solvent power with no comparison with that observed in
this same fluid in the compressed gas state. Likewise
for the so-called "subcritical" liquids, that is to say
in a state characterized either by a pressure greater
than the critical pressure and by a temperature less
than the critical temperature in the case of a pure
body, or by a pressure greater than the critical
pressures and a temperature less than the critical
temperatures of the components in the case of a mixture
(Michel PERRUT, les Techniques de 1'Ingenieur
"Extraction par fluide supercritique", J2 770 - 1 to
12, 1999).
The large and modulable variations in the
solvent power of these fluids are in fact used in
numerous methods of extraction (solidlfluid),
fractionation (liquid/fluid), analytical or preparative
chromatography, treatment of materials (ceramics,
polymers, and the like). Chemical or biochemical
reactions are also carried out in such solvents.
For about ten years, numerous studies have
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been undertaken in order to obtain the spray-drying of
liquid or solid substances using methods based on the
properties of supercritical fluids, such as methods of
recrystallization by antisolvent effect or the rapid
expansion of supercritical solutions, leading to the
production of powders of.very fine particle size, of
the order of 0.1 to 10 micrometers, or even of complex
powders where the active ingredient is dispersed in an
excipient or encapsulated in a protective agent.
Likewise, various spraying methods have been developed
using a supercritical fluid, in particular for
dispersing droplets of paint, of adhesive or of coating
as described in patents US-5009367; US-5057342;
US-5066522; US-5254260 and US-5197800 as well as in
patents EP-0 388 923, EP-0 388 915, EP-0 421 796 and
EP-0 506 067. It is thus possible to substantially
reduce, by around 30 to 60~, the organic solvent
content of paints, reducing by as much the emissions of
volatile organic compounds resulting therefrom, without
the final quality of the coating, and in particular its
appearance, being thereby impaired.
One of the main advantages of the methods
using fluids at supercritical pressure lies in the ease
of carrying out the separation between the solvent (the
fluid) and the extracts and solutes, as has been
described in numerous publications and, for some
important aspects of implementation, in French patent
CA 02390132 2002-05-02
FR-2 592 488. The advantageous properties of these
fluids have in fact been used for a long time in solid-
fluid extraction and liquid-fluid fractionation, as is
described in the abovementioned article. In addition,
5 it is also advantageous to note that a solvent at
supercritical pressure not only has the property of
dissolving certain compounds, a property used in the
methods which have just been cited, but also of
substantially dissolving in liquids and certain solids
such as polymers. This capacity is used in some methods
of spraying, impregnation or production of polymer
foams. Thus, it is known that carbon dioxide maintained
at supercritical pressure and at a temperature in the
region of its critical temperature, can dissolve in
common thermoplastic polymers in an amount of 10 to 30~
by mass according to the nature of the polymer, in fact
causing a substantial swelling of the polymer and a
profound change in its physical properties, with a
considerable deterioration of its mechanical properties
and a reduction in its glass transition temperature
which may be as much as 40°C in some cases. It is also
known that a sharp decompression of this solution of
fluid at supercritical pressure in a solid or a liquid
may be achieved in a spray-drying nozzle and thus lead
to the production of solid particles as has been
described in particular in patent application
WO-95/21688 and in various publications citing, fox
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example, results of spraying polyethylene glycol
(Weidner E., Steiner R., Knez. Z., in "High Pressure
Chemical Engineering", Elsevier 1996, ISBN 0-444-82475-
8, p. 223-228).
The physicochemical properties of carbon
dioxide as well as its critical coordinates (critical
pressure: 7.4 MPa and critical temperature: 31°C) make
it the supercritical fluid of choice used as preferred
solvent in numerous applications especially since it
exhibits no toxicity and is available at very low cost
and in very large quantity. A nonpolar solvent, carbon
dioxide brought to supercritical pressure is sometimes
also supplemented with a cosolvent consisting of an
organic solvent capable of notably modifying the
solvent power of this dioxide especially in relation to
molecules having some polarity.
However, it has now been found, surprisingly,
that it is possible to carry out the film-coating of
tablets starting with a suspension of a film-coating
agent in a fluid at supercritical pressure which is
sprayed onto the tablets to be film coated.
Consequently, the invention relates to a
method for film-coating tablets, a method according to
which a suspension of the film-coating agent in a fluid
at supercritical pressure is sprayed over the tablets
in question.
Thus, the method of the invention is
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characterized by the use of the particular properties
of fluids at supercritical pressure in relation to
polymers and liquids in which they substantially
dissolve, which, according to the invention, will allow
easy production of a very homogeneous suspension of the
film-coating agent in the fluid, and on the use of
these fluids at supercritical pressure as agents for
spraying through a nozzle, or any other device which
makes it possible to create a very high pressure drop
and to thus allow spraying of the suspension in which
they are dissolved.
The method of the invention can be carried
out by first preparing, by mechanical stirring, a very
homogeneous suspension of a film-coating agent in a
1b fluid at supercritical pressure, generally carbon
dioxide, and then spraying this suspension as a fine
mist of droplets where the fluid will be immediately
discharged when the operation is carried out under
suitable temperature and pressure conditions, that is
to say at a temperature of between room temperature and
60°C and at a pressure of between atmospheric pressure
and 200 bar. When the method of the invention is
carried out under pressure, the procedure is generally
carried out between 30 and 200 bar, preferably at a
pressure of between 100 and 200 bar, and generally at a
temperature of between 30 and 60°C. Preferably, the
film-coating operation is performed under normal
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temperature and pressure conditions, that is to say at
room temperature and at atmospheric pressure.
The distribution of this film coating on the
tablets will be all the better if the latter are
subjected to continuous stirring as is carried out
according to conventional film-coating techniques in
drums rotating around their horizontal axis.
The expression "film-coating agent" is
understood to mean any compound generally used to this
effect, that is to say a compound which is capable, on
covering the tablet, of forming a film coating or a
coating, or alternatively a mixture of such compounds.
This film coating may have in particular the effect of
providing mechanical protection of the tablet against
disintegration or crushing or alternatively of
constituting an enteric coating or a coating capable of
causing, after administration of the tablet, a
prolonged release of the active ingredient containing
it.
Usually, this film-coating agent is chosen
from cellulose derivatives such as methyl cellulose,
ethyl cellulose, propyl cellulose; hydroxylated
cellulose derivatives such as hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose; a microcrystalline
cellulose; a polyacrylate such as a copolymer of
acrylate, an ester of acrylic acid and of methacrylic
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acid, a methylmethacrylic ester, a polyhydroxyethyl
rnethacrylate; a polyvinyl alcohol; a polyethylene; a
polypropylene; a polyethylene glycol; a polystyrene; a
polyacrylamide; an ethylvinyl acetate polyvinyl acetate
copolymer; a phthalate polyvinyl acetate copolymer; a
polyvinylpyrrolidone; titanium oxide; a wax.
The film-coating agent in question may be
introduced as it is into the supercritical fluid or
preferably in the form of a suspension in one or more
appropriate solvents generally of low molecular weight
chosen, for example, from C1-C4 alcohols such as ethanol
or isopropanol and C3-C6 esters such as ethyl acetate.
Ethanol however constitutes a particularly preferred
solvent.
In addition, the proportions of the
solvent(s~ and of film-coating agent in the suspension
will be suitably chosen so as to avoid as far as
possible any effects of blocking the device for the use
of the method of the invention in particular nozzles
for spray-drying the suspension of film-coating agent
in the fluid at supercritical pressure. For this
reason, the quantity of film-coating agent in
suspension in the solvent in question can vary from 5~
to 30~ of the weight of the total suspension, in
particular from 10~ to 20~.
According to a variant of this method, the
suspension of the film-coating agent in the fluid at
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supercritical pressure may be facilitated by the
addition, to this fluid, of one or more appropriate
liquid cosolvents. This cosolvent, which is also of low
molecular weight, may be selected from the solvents
5 mentioned above for the constitution of a suspension of
the film-coating agent in an appropriate solvent.
In this variant, the film-coating agent may
be introduced as it is into the fluid at supercritical
pressure containing one or more cosolvents or on the
10 contrary in the form of a suspension in one or more
solvents as described above.
In addition, the quantity of film-coating
agent in the fluid at supercritical pressure will not
exceed 30~ of the mass thereof.
Usually, a cosolvent identical to that which
serves to prepare the suspension of the film-coating
agent, in particular ethanol, is used in this variant.
The method of the invention thus described
has in particular the advantage of avoiding the use of
an aqueous suspension of film-coating agent, which
eliminates contact between water and the tablets and
subsequent drying. Likewise, it is thus possible to
avoid using a suspension of film-coating agent in an
organic solvent, which eliminates the handling of
potentially toxic organic solvents, the substantial
emission of volatile organic compounds and the risk of
contamination of the tablets with traces of these
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solvents. According to particularly favorable and
preferred embodiments of the method which is the
subject of the invention, certain quantities of ethanol
are used to modify the behavior of the fluid at
supercritical pressure or to initially disperse the
film-coating agent in order to make its handling
easier.
However, the low risk of toxicity of ethanol
is absolutely not comparable to that of most other
organic solvents, and the quantities emitted from this
alcohol into the atmosphere may be very limited
according to certain implementations of the method.
Other characteristics and advantages of the
method of the invention will emerge during the
following description with reference to the
accompanying drawings in which:
- Figure 1 schematically represents a plant
for the film coating of tablets comprising a reactor
for preparing the suspension of film-coating agent in a
fluid at supercritical pressure and a film-coating
drum, this plant being intended for batch use of the
method of the invention.
- Figure 2 schematically represents a plant
for film-coating tablets which is intended for a batch
use under pressure of the method of the invention, more
precisely a film-coating drum capable of operating at
high pressure as well as a device for recycling the
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supercritical fluid.
- Figure 3 schematically represents a plant
for film-coating tablets and more precisely a film-
coating drum for continuous use of the method of the
invention.
- Figure 4 schematically represents a plant
for film-coating tablets and more precisely a film-
coating drum capable of operating at high pressure for
continuous use of the method of the invention.
Thus, during batch use of the method of the
invention, in a plant as represented in Fig 1, the
chosen solvent fluid (1), for example carbon dioxide,
is compressed by means of a positive displacement
vacuum pump (2) with a membrane and an adjustable
output. By virtue of the pump (3) of the same type,
whose output may be adjusted, a cosolvent (4)
consisting of an organic liquid solvent, preferably
ethanol, may be added, if necessary, to the solvent
fluid. The mixture thus compressed at the desired
supercritical pressure is then heated at the chosen
temperature, generally a temperature in the region of
the critical temperature of the solvent fluid, this
being in a heat exchanger (5) consisting of a double
tube, of which the outer tubular part is flushed with
hot water at a suitable temperature.
This mixture is then introduced into a
reactor (6) equipped with a stirrer (7) moved by an
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electric motor (8) via a magnetic driving system (9).
The suspension of film-coating agent (10)
being stirred is also introduced into the reactor (6)
by means o.f a pump (11) of the same type as the
preceding ones.
This suspension generally consists of an
organic solvent in which the various components of the
film-coating agent are dispersed, this solvent being
favorably the same as that which is used as cosolvent
in the solvent fluid at supercritical pressure.
The rapid rotation of the stirrer (7) then
makes it possible to prepare a homogeneous suspension
of the film-coating agent in the solvent mixture
brought to supercritical pressure.
This suspension is then sent to the film-
coating drum (13) in which it is decompressed via a
spray-drying nozzle (12), the conduit for conveying the
suspension between the reactor (6) and the nozzle (12)
being heated by an electric cord (14) in order to avoid
the precipitation of the film-coating agent and the
blocking of this conduit. The sharp reduction in
pressure causes the formation of very fine droplets of
a liquid consisting of film-coating agent dissolved or
dispersed in the organic solvent. These droplets, when
they collide with the tablets, cover them with a film
which is all the more homogeneous if these tablets are
constantly stirred by the rotation of the film-coating
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drum (13). This drum installed in a vessel (18)
consists of a cylinder with a horizontal axis whose
walls are perforated with holes (15) so as to allow
passage of an air stream (16) brought to a temperature
of 50 to 60°C.
The organic solvent is rapidly carried by the
solvent fluid brought to atmospheric pressure and by
the hot air stream (16) which makes it possible to
provide the enthalpy necessary for complete
vaporization of the organic solvent, the gas formed
being evacuated by the conduit (17) linked to a vent.
The film of film-coating agent then forms
uniformly and rapidly because of, on the one hand, the
complete elimination of the organic solvent and of the
solvent fluid, and on the other hand, the continuous
stirring of the tablets generally maintained at
atmospheric pressure or at a similar pressure, and at
room temperature, or at a similar temperature,
allowing, in this manner, good distribution of this
agent over the entire surface of these tablets.
According to one variant of the previous
batch implementation, it is possible to use a plant as
represented in Fig 1 but modified according to Fig 2,
that is to say a plant in which the film-coating drum
(13) is installed in a vessel (18) designed to
withstand a pressure of at least 200 bar.
In this embodiment, the operation of
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preparing the suspension of film-coating agent in the
solvent fluid at supercritical pressure is performed in
the same equipment as above, as well as the spraying of
this suspension in the film-coating drum containing the
5 tablets maintained under pressure generally at a
pressure of between 30 and 200 bar, for example a
pressure of the order of 150 bar and at an appropriate
temperature which is generally between 30 and 60°C, for
example between 45 and 55°C. However, no hot air is
10 injected as in the batch method above but a stream of
solvent fluid (1) brought to a temperature of 30 to
60°C. The stream leaving the film-coating drum,
consisting of a mixture of solvent fluid, of cosolvent
and of solvent used for preparing the solution of film-
15 coating agent, is then decompressed, at a pressure of
the order of 45 bar, via an overflow-type valve (19).
This decompression causes demixing of the mixture which
is admitted into a set of separators (20) (21)
consisting, according to the system described in the
previously mentioned patent FR 2592488, of cyclonic
chambers allowing complete separation of the liquid
phase and of the gaseous phase with supply of heat via
the walls of the separators. To this effect, the jacket
of these separators is filled with hot water, which
makes it possible to supply the enthalpy required to
bring about vaporization of the solvent fluid. The
liquid phase is then drawn off at atmospheric pressure
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via a system of lock chambers (22) (23) operating
according to the system described in the already cited
patent FR 2592488. The solvent fluid thus considerably
freed of the solvent and cosolvent used may be
recycled. To this effect, it is liquefied in a double-
tube condenser (24) in which the outer tubular part is
run through by a mixture cooled to around 0°C such as a
water/ethylene glycol mixture.
The solvent fluid is then stored in the
liquid state at around 5°C in a reservoir (25) whose
level is stably maintained by topping up with solvent
fluid from an external cistern (26), before being
recycled by the pump (2).
The uses described above may also be modified
so as to make the method of the invention completely
continuous.
Consequently, another subject of the
invention relates to a method of film-coating as
described above in which the spraying is carried out
continuously in a film-coating drum whose axis is
inclined relative to the horizontal, for example
inclined by 5°, allowing continuous circulation of the
tablets introduced into the top part of the drum and
recovered after film-coating in the bottom part of this
drum.
According to a first continuous use, it is
possible to use a plant as represented in Fig 1 but
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17
modified according to Fig 3, that is to say a plant
whose film-coating drum (13) is slightly inclined
relative to the horizontal in order to allow not only
the rotation of the tablets but also their slow
longitudinal movement in the drum. The length and
obliqueness of the rotating unit (13) are, in addition,
calculated so as to maintain a residence time suitable
for a complete and rapid film-coating.
Moreover, a hopper (27) and a vessel (28) are
connected, one to the inlet situated upstream and to
the top part of the drum (13) in order to allow the
semicontinuous introduction of the tablets, the other
downstream and to its bottom part so as to recover the
film-coated tablets.
In addition, a line (29) of several nozzles
(12) arranged in parallel allows continuous spraying
over the tablets moving in the rotating drum.
In such a system, it will be possible, by
modifying the size of the orifices of the nozzles (12)
as well as by the obliqueness of the drum, to modify
the time for complete spray coating, according to the
expected result. In addition, the gaseous stream
leaving the film-coating drum is treated by either of
the recovery/recycling methods forming part of the
batch implementations described above.
According to a variant of the continuous
method above, the spraying is carried out continuously
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in a film-coating drum whose axis is inclined relative
to the horizontal, for example inclined by 5°, allowing
continuous circulation of the tablets maintained under
pressure in the drum, for example at a pressure of
between 30 and 200 bar and at an appropriate
temperature, for example at a temperature of between 30
and 60°C, these tablets being introduced into the film-
coating drum by means of a lock chamber system situated
upstream and at the top part of said drum and
recovered, after film-coating, downstream by means of a
lock chamber system situated at the bottom part of this
drum, these lock chamber systems functioning semi-
continuously so as to maintain a pressure in the drum
in question, for example a pressure of between 30 and
200 bar.
Thus, according to a second continuous
implementation, it is possible to use a plant as
represented in Fig 2 but modified according to Fig 4,
that is to say a plant in which the film-coating drum
(13) is placed in a vessel (18) which can withstand a
pressure of 200 bar.
Its axis, like that of the vessel under
pressure (18) containing it, is slightly inclined
relative to the horizontal in order to not only allow
the rotation of the tablets but also their slow
longitudinal movement in the drum. The length and
obliqueness of the rotating unit are in addition
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19
calculated in order to maintain a residence time
suitable for a complete and rapid film-coating.
Moreover, two lock chambers (30) and (31) are
connected, one to the inlet situated at the top part of
the drum (13), the other at its bottom part. They can
be placed under pressure by a stream of solvent fluid
derived from the latter which allows flushing of the
drum (13). Moreover, a line (29) of several nozzles
(12), arranged in parallel and around the axis of the
drum (13), carries out continuous spraying over the
moving tablets in the rotating drum.
In such a system, it is possible, by
modifying the size of the orifices of the nozzles as
well as by the obliqueness of the drum, to modify the
total film-coating time, according to the expected
result. Moreover, this system allows the continuous
introduction of tablets via the lock chamber (30) and
their recovery in a similar quantity via the lock
chamber (31) and the vessel (28) with a view, for
example, to their on-line placing in bags. Finally, as
in the preceding batch implementations, the gaseous
stream leaving the film-coating drum may be treated by
the recovery/recycling methods described therein.
The following nonlimiting examples illustrate
the method of the invention.
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EXAMPLE 1
Film-coating of pharmaceutical tablets
containing valproic acid and its sodium salt (batch
route)
5 There is carried out, in a plant as
illustrated in Fig 1, the film-coating of a batch of
scored tablets having a mean unit mass of 730 mg
containing a pharmaceutically active ingredient
consisting of valproic acid and its sodium salt as well
10 as an excipient consisting of cellulose derivatives,
silica and saccharin sodium with a film-coating agent
consisting of a mixture containing, in equal parts, a
polyacrylate, a polyethylene glycol, a cellulose
derivative of the methylhydroxypropyl cellulose type,
15 talc and titanium oxide, this film-coating leading to
delayed assimilation of the medicament.
While stirring for 12 hours, the film-coating
agent is first of all suspended in absolute ethanol in
an amount of 250 g of this agent per 750 g of ethanol.
20 Two liters of this suspension are then introduced into
the reactor (6) and it is brought into contact with
pure carbon dioxide maintained at 150 bar and 45°C.
This mixture is kept stirred by means of a marine
anchor-type stirrer rotating at the speed of
600 revolutions per minute.
After stirring for 20 minutes, the suspension
thus obtained is sent to the film-coating drum (13)
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21
consisting of a cylinder with a horizontal axis having
a diameter of 0.48 m and a length of 0.32 m, into which
kg of tablets are introduced. The suspension is
abruptly decompressed to atmospheric pressure through a
5 nozzle (12) whose orifice has a diameter of 350 Vim. The
film-coating drum is set in rotation at a speed of
4 revolutions per minute and it is flushed with a
stream of 100 m3/h of hot air at 50°C.
At the end of 5 minutes, after having sprayed
about 550 g of suspension, the spraying is stopped and
the rotation of the drum and the supply of hot air are
maintained for 5 minutes in order to remove the last
traces of ethanol and of carbon dioxide.
After this operation, the hot air flushing is
stopped and the rotation of the drum is stopped in
order to allow recovery of the tablets which are then
observed with a binocular lens and precisely weighed.
The average mass of a film-coated tablet is thus up to
748 mg and practically all of these tablets exhibit
excellent surface appearance, similar to that obtained
during the use of film-coating by the method
conventionally used starting with an aqueous suspension
of the film-coating agent. This film-coating operation
according to the earlier method requires an operation
time of the order of 110 minutes on the same film-
coating drum as that used above, that is 10 times more
time than by using the method which is the subject of
CA 02390132 2002-05-02
22
the present invention.
EXAMPLE 2
Film-coating of pharmaceutical tablets
containing valproic acid and its sodium salt (batch
route)
The film-coating of a batch of tablets
identical to those used in example 1 with an identical
film-coating agent is carried out in a plant as
illustrated in Fig 2.
The film-coating drum (13), while similar to
that used in the plant of Fig 1, is nevertheless
installed in a cylindrical chamber (18) designed to
withstand a pressure which may be up to 200 bar, the
drum being rotated via a magnetic drive system allowing
good leaktightness at high pressure.
There are first of all carried out, in a
manner similar to that used in example 1, the
preparation of the initial suspension of film-coating
agent in ethanol and then the preparation of the
suspension in the reactor (6) in the presence of carbon
dioxide at supercritical pressure with nevertheless the
pressure inside this reactor being maintained at
190 bar.
After loading 5 kg of tablets, the unit is
closed and filled with carbon dioxide at 60 bar and
50°C. A stream of carbon dioxide is maintained under
these pressure and temperature conditions for a flow
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23
. rate of 100 kg/h, the fluid leaving the drum then being
decompressed to about 45 bar in the pressure-reducing
valve (19), sent to the separator (20) and (21) and
then recycled as described above.
When the equilibrium of the conditions has
been reached, the spraying of the suspension prepared
in the reactor (6) is started in the spraying drum (13)
for 5 minutes via a nozzle identical to that used in
example 1. Also as in this preceding example, the
flushing with carbon dioxide and the rotation of the
drum (13) are maintained for 5 minutes after stopping
the spraying, and then the fluid contained is emptied
and the vessel (18) and the drum (13) are opened in
order to recover the tablets. The weighing and the
examination of the tablets give results very similar to
those obtained in example 1 or those obtained using the
conventional method, with an average unit mass of
751 mg. However, unlike example 1, the emission of
ethanol into the atmosphere was at least divided by 10,
most of the ethanol being recovered in the separators
(20-21) and drawn off from the lock chamber (22-23) at
atmospheric pressure. A small part of this alcohol is
carried by carbon dioxide and is therefore immediately
recycled into the method. The emission of solvent into
the atmosphere is limited to those emitted during the
discharge from the film-coating drum at the end of the
operation, and the carbon dioxide emissions are also
CA 02390132 2002-05-02
24
divided by at least 10 relative to those observed in
example 1.
EXAMPhE 3
Film-coating of pharmaceutical tablets
containing valproic acid and its sodium salt
(continuous route)
The film-coating of a batch of 365 kg of
tablets identical to those used in example 1 with an
identical film-coating agent is carried out in a plant
as illustrated in Fig 1 and 3.
To this effect, the initial suspension of
this agent in ethanol is first of all prepared, as
described in example 1, followed by the suspension in
the reactor (6) in the presence of carbon dioxide at
supercritical pressure. Likewise, an equipment similar
to that used in example 1 is used for carrying out this
film-coating operation.
However, the film-coating drum (13) having a
diameter of 0.48 m and a length of 1.50 m is inclined
at 5° relative to the horizontal. Furthermore, the
equipment provides the possibility of semicontinuously
introducing 2 to 3 kg of tablets by means of a hopper
(27) connected to the drum (13) by a vertical tubing
having a diameter of 0.05 m connected to the uppermost
part of the drum (13) and to collect therefrom in the
vessel (28), about every two minutes, a similar
quantity by a vertical tubing having the same diameter
CA 02390132 2002-05-02
as the preceding one, connected to the bottommost part
of the drum (13).
The film-coating method may be carried out
practically continuously, the reactor (6) being fed, on
5 the one hand, by a flow rate of suspension of film-
coating agent of 10 kg/h by the pump (5) regulated by a
level indicator placed in the reactor (6) and, on the
other hand, with carbon dioxide at supercritical
pressure by the pump (2) at the flow rate required to
10 maintain a pressure of 150 bar in the reactor in
question.
The spraying is carried out continuously
through a line (29) of four nozzles (12) in parallel,
similar to those used in the preceding examples, these
15 nozzles being arranged along the axis of the drum (13).
The film-coating operation is carried out in
a manner similar to that described in example 1: the
film-coating drum is set in rotation at a speed of
4 revolutions/minute and is flushed with a stream of
20 100 m3/h of air (16) heated to 50°C. For a period of
6 hours, it was thus possible to film-coat the batch of
365 kg of tablets in a very advantageous manner, the
average mass of the tablets after treatment being
752 mg.
CA 02390132 2002-05-02
26
EXAMPLE 4
Film-coating of pharmaceutical tablets
containing valproic acid and its sodium salt
(continuous route)
The film-coating of a batch of 345 kg of
tablets identical to those used in example 1 with an
identical film-coating agent is carried out in a plant
as illustrated in Fig 1 and 4.
To this effect, the initial suspension of
this agent in ethanol is first of all prepared, as
described in example 1, followed by the suspension in
the reactor (6) in the presence of carbon dioxide at
supercritical pressure.
Likewise, an equipment similar to that used
in example 2 is used for carrying out this operation.
However, the film-coating drum (13) having a diameter
of 0.48 m and a length of 1.50 m, placed in a vessel
(18) containing it, is inclined at 5° relative to the
horizontal. Furthermore, two lock chambers of 10 liters
(30) and (31) are connected to the inlet and to the
outlet of the drum (13). These lock chambers may be
placed under pressure by a carbon dioxide stream
derived from that which provides the flushing of the
drum (13) and make it possible to semicontinuously
introduce from 2 to 3 kg of tablets and to extract a
similar quantity therefrom, about every two minutes.
The film-coating method may be carried out
CA 02390132 2002-05-02
27
practically continuously, the reactor (6) being fed, on
the one hand, by a flow rate of suspension of film-
coating agent of 10 kg/h by the pump (5) regulated by a
level indicator placed in the reactor (6) and, on the
other hand, with carbon dioxide at supercritical
pressure by the pump (2) at the flow rate required to
maintain a pressure of 190 bar in the reactor in
question.
The spraying is carried out continuously
through a line (29) of four nozzles (12) in parallel,
similar to those used in the preceding examples, these
nozzles being arranged along the axis of the film-
coating drum.
The decompression of the fluid stream derived
from the drum (13), the separation and the recovery of
ethanol via the separators (20) and (21) and the lock
chambers (22) and (23) as well as the recycling of
carbon dioxide are carried out in a manner similar to
that described in example 2.
For a period of 6 hours, it was thus possible
to film-coat the batch of 345 kg of tablets in a very
satisfactory manner, with a total ethanol emission of
5.8 kg and a carbon dioxide consumption of 183 kg.
EXAMPLE 5
Film-coating of tablets containing
clopidogrel
Using the same method as described in
CA 02390132 2002-05-02
28
example 2, a batch of 6 kg of tablets having an average
unit mass of 240 mg comprising clopidogrel as active
ingredient was film-coated with a film-coating agent
consisting of a mixture containing a phthalate
polyvinyl acetate copolymer, starting with a suspension
of 400 g of this film-coating agent in 1 600 g of
ethanol. This suspension is brought into contact with
pure carbon dioxide maintained in the supercritical
state under temperature and pressure conditions of 50°C
and 150 bar and the film-coating operation is carried
out for 20 minutes.
At the end of this operation, tablets having
an average mass of 243.6 mg are obtained. Practically
all these tablets exhibit satisfactory film-coating.
